By the time diseases of the retina are detected, serious damage has often already been done. An advanced optical imaging instrument utilizing adaptive optics can be used to directly visualize the cellular structure of the retina in the living human eye. Adaptive optics is a technology for measuring and correcting the optical imperfections in the human eye. When adaptive optics is combined with an imaging platform, highly detailed images of the human retina can be acquired. Our research utilizes this technology to image cells in patients eyes through the recently-established Adaptive Optics Clinic within the NIH Clinical Center. Processing of adaptive optics is highly time-consuming and labor intensive. Currently, there are very few publicly-available tools for handling of adaptive optics data. We have been actively developing novel computational tools for the computer aided analysis of adaptive optics imaging data which will greatly enhance and accelerate our progress towards assembling a normal database of adaptive optics imaging data. Examples of such tools include the automated identification, segmentation, and tracking of photoreceptor neurons on split detection adaptive optics images. We have made progress towards developing similar tools for RPE imaging which will be important for development of quantitative biomarkers. These tools are becoming increasingly important for unraveling the clinical meaning of our images, which contain unprecedented levels of detail that can be difficult to interpret otherwise. Our long-term goal is to make the tools that we develop publicly-available to facilitate large-scale data science as well as data reproducibility. We remain very interested in exploring new technologies for improving our state-of-the-art, custom-built adaptive optics instrument in the NEI eye clinic with the overarching goal of augmenting the translational research capabilities at the NIH Clinical Center. We have recently invented new methods based on adaptive optics near-infrared autofluorescence (AO-IRAF) and adaptive optics enhanced indocyanine green (AO-ICG) imaging to simultaneously image the retinal pigment epithelial cells alongside the photoreceptors directly inside the living human eye. Characterizing how these images look in healthy and diseased eyes may lead to new insights about the pathophysiology of retinal diseases. On the instrumentation front, we are collaborating with Dr. Zhang of the University of Alabama, Birmingham to explore high speed approaches for adaptive optics retinal imaging. We continue to collaborate with Dr. Yang of the University of Rochester and Drs. Pursley and Pohida, CIT, to implement state-of-the-art, real-time eye tracking capabilities for adaptive optics retinal imaging, as well as with Drs. Hammer and Liu of the FDA to explore complementary advanced imaging modalities compatible with adaptive optics. Progress towards these projects are facilitated by ongoing collaborations with Howard Metger and Robert Clary (custom fabrication, NIH machine shop), and with the NIH Library for 3D printing of components related to various modules within the custom-built adaptive optics instrument. Finally, through collaboration with Drs. Huryn, Cukras, Zein, Brooks, Wong, Chew, Wiley, Hufnagel, and other NEI clinicians, we are beginning to explore the manifestation of sight-threatening diseases at the cellular level. We are developing a translational imaging framework to cross-validate our findings using microscopy, through collaboration with Drs. Fariss, Smelkinson, and Schwartz. Translation of our technology and tools into these patients will lead to the ability to monitor the progression of disease in actual patients at the cell-to-cell level.